Imaging studies are the cornerstone for tumor localization in patients with Cushing's syndrome caused by ectopic adrenocorticotropin hormone (ACTH) secretion (EAS). Computed tomography (CT) and magnetic resonance imaging (MRI) are used most commonly to localize the source of EAS. However, in 30-50 percent of patients with EAS the source of ACTH secretion cannot be found despite repeated studies over time. Up to half of these patients do not respond to medical therapy of hypercortisolism and must undergo bilateral adrenalectomy with lifelong replacement therapy. Thus, there is a need for improved imaging techniques to identify ACTH-secreting tumors. Nuclear medicine techniques enable in vivo imaging of physiological and pathophysiological processes, and among these techniques, positron emission tomography (PET) studies are increasingly used in oncology. We previously evaluated the utility of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) or 111In-DTPA-D-Phe-pentetreotide (OCT) at higher than standard doses of radionuclide (18 mCi;H-OCT), and found that FDG-PET did not detect tumors that were occult on CT/MRI. H-OCT rarely identified a lesion. Thus, conventional modalities of CT and MRI should be used to image the neck, thorax, and abdomen in these patients. FDG-PET does not provide additional information. H-OCT may be useful when other imaging modalities fail to localize the ACTH-secreting tumor. Currently we are extending these studies to evaluate the utility of 18F- L-3,4-dihydroxyphenylalanine (18F-DOPA) PET to identify these tumors. This compound is a precursor for serotonin production in neuroendocrine tumors, and thus is a good candidate for PET examination since most occult ACTH-secreting tumors are neuroendocrine. We have also evaluated whether serum CgA, CT, ProCT, or NProCT values to distinguish CD from EAS in a prospective pilot study. Serum ProCT, NProCT, and CgA were measured in six patients with occult EAS diagnosed by IPSS, 25 CD patients, and 11 patients with histologically proven EAS. Nine EAS patients (53%) had at least one value above the reference range, including CgA alone (n = 4), ProCT alone (n = 3), CgA and ProCT (n = 1), and NProCT and ProCT (n = 1). Of nine (36%) CD patients with one or two abnormal values, seven had increased ProCT only, one had increased NProCT only, and one had increased CgA and ProCT. CgA had a positive predictive value of 83% and a negative predictive value of 70% for the diagnosis of EAS;other markers showed less discrimination. On pituitary magnetic resonance imaging, no EAS patient had an abnormality, whereas 21 of 25 patients with CD had a mass. These preliminary results suggest that an abnormal CgA and normal pituitary magnetic resonance imaging favor the diagnosis of EAS, but normal tumor markers do not exclude the diagnosis. While detection of pituitary tumors with magnetic resonance imaging (MRI) may reduce diagnostic costs and improve surgical outcomes for patients with Cushing's disease, the optimal T1-weighted spin echo MRI protocol remains unknown. We hypothesized that specific MR scanning parameters influence detection of corticotropinomas. We found that 21 of 84 consecutive patients with Cushing's disease had a falsely negative initial pituitary MRI study and a lesion identified subsequently at the NIH Clinical Center. In 18 patients with available scans, matrix sizes were similar and nearly all had 3 mm slice thickness. Parameters that differed between the NIH and outside scans were: TR (400 ms vs. 492+/-19 ms, P = 0.0002);TE (10.3 +/- 0.5 vs. 17.2 ms +/- 1.2 ms, P = 0.0003);FOV (12x12 cm vs.17+/-0.6 x 18+/-0.7 cm, P<0.0001). Immunohistochemistry of tumors resected at transsphenoidal surgery confirmed all to be corticotropinomas. We conclude that MRI technique, particularly FOV and TR/TE value, influences results and recommend that endocrinologists consider pituitary MRI parameters when interpreting the results. The glucocorticoid antagonist mifepristone blocks cortisol action and thus might be an effective treatment of Cushing's syndrome. This hypothesis is being tested in an ongoing clinical trial of patients with presumed ectopic ACTH secretion.